In the developed world, the current therapeutic choices for treatment of hemophilia patients comprise prophylactic and on-demand replacement therapy (Lofqvist T. et al., J. Intern. Med. 1997; 241:395-400) with either plasma-derived or recombinant coagulation factor concentrate (Lippert B. et al., Blood Coagul. Fibrinolysis. 2005; 16:477-485). Standard treatment for Hemophilia is infusions of protein concentrates to replace the defective clotting factor. The amount infused depends upon the severity of bleeding, the site of the bleeding, and the body size of the patient. People with severe forms of the disease may be treated by regular prophylactic infusions. The outcome is good with treatment and management, so most people with hemophilia are able to lead relatively normal lives. However, the high cost and limited availability of the recombinant protein make dosing of clotting factors a crucial issue in the treatment of hemophilia. In addition, the plasma-derived products run the risk for HIV and hepatitis B and C transmission, and the half-life of the infused protein in a patient is short, which results in the necessity for fairly frequent infusions (White G. C. et al., Transfus. Sci. 1998; 19:177-189).
Other treatments, such as gene therapy and tissue implant techniques are also under study as possible treatments (Hough C. et al., J. Thromb. Haemost., 2005; 3:1195-1205). One clinical trial of gene therapy in hemophilia patients showed only transient therapeutic increments of clotting factor expression due to generation of antibody against delivering vehicle (Manno C. S. et al., Nat. Med. 2006; 12:342-347). Therefore, gene therapy remains an investigational method with many obstacles to overcome before it can be widely used as treatment for hemophilia.
Hemophilia B is caused by a deficiency of a blood plasma protein called factor IX that affects the clotting property of blood. The disorder is caused by an inherited X-linked recessive trait, with the defective gene located on the X chromosome. Thus, the disorder occurs primarily in males. Hemophilia B occurs in about 1 out of 30,000 men.
Human factor IX is a vitamin K-dependent zymogen which plays an important role in blood coagulation. Factor IX circulates as a 415-amino acid single chain zymogen with a molecular mass of 55,000 daltons and is present in normal plasma at approximately 5 μg/ml.
Recombinant factor IX products offer greatly reduced risk for HIV and hepatitis B and C transmission. If recombinant factor IX with enhanced clotting activity can be generated through genetic engineering of factor IXDNA, it will not only lower the cost for the clotting factor but also reduce the dose of it in managing patients with hemophilia. Moreover, this method will also provide a more efficient tool for gene therapy trials in patients with hemophilia.